How Effective Are Antidepressants?

Key Takeaways

• This article provides an evidence-based review + clinical opinion of antidepressant effectiveness and tolerability, written by a psychiatrist with 35+ years of clinical experience treating major depressive disorder and complex chronic illness.
• It analyzes the landmark 2009 and 2018 network meta-analyses by Cipriani et al., including 522 randomized controlled trials (116,477 participants) comparing 21 antidepressants.
• Conclusion: All 21 antidepressants studied were statistically more effective than placebo for major depressive disorder in adults.
• Antidepressants with the best balance of effectiveness and acceptability: escitalopram, sertraline, mirtazapine and vortioxetine.
• The evidence suggests paroxetine, amitriptyline, and venlafaxine have high effectiveness but lower tolerability. Why I disagree.
• Antidepressants reduce relapse risk by approximately 70% when continued for up to 3 years.
• Important caution: Antidepressants do not treat the core symptoms of ME/CFS and should not be used for this purpose unless a co-existing depressive disorder is present.
• Best outcomes occur when medication is integrated into a comprehensive, individualized treatment plan including psychotherapy, lifestyle support, and careful monitoring.

 Full Blog

I am a psychiatrist with 35 years-experience treating people with mental disorders. I am frequently asked and will answer in the blog below:

1. Do antidepressants work?
2. If so, which are most effective? and,
3. Given we in the complex chronic disease community are generally more sensitive to side effects, which are best tolerated?

In the first edition of my manual Let Your Light Shine Through, I answered the question of whether antidepressants work by citing a large 2009 study by Andrea Cipriani and colleagues from Oxford university (A. Cipriani et al., 2009). Based on that paper I concluded the following:

The most effective antidepressant drugs at that time based on head-to-head comparisons of comparable doses were mirtazapine (Remeron®), escitalopram (Cipralex®), venlafaxine (Effexor®), and sertraline (Zoloft®).

The best tolerated antidepressant drugs based on head-to-head comparisons of comparable doses were buproprion (Wellbutrin®), citalopram (Celexa®), escitalopram (Cipralex®), and sertraline (Zoloft®).

As new antidepressants have been released, I increasingly get asked about them. You can imagine my delight when an update was published by Cipriani’s group in 2018 allowing me to give evidence-based updated guidance to patients. A more detailed discussion of this updated analysis appears in the second edition of Let Your Light Shine Through. However I don't agree with some of the findings. Keep reading to learn why.

What Are the Most Effective Antidepressants Meta-Analysis.

This landmark study, also by Cipriani and colleagues, compared effectiveness (does it work?) and acceptability (is it tolerated?) of the most commonly used antidepressants for major depressive disorder in adults (Andrea Cipriani et al., 2018). It updates and expands upon the 2009 study.

The 2018 network meta-analysis included 522 randomized controlled trials (116,477 participants) comparing 21 antidepressants with placebo and with each other. Effectiveness was defined as a ≥50% symptom reduction; acceptability was based on dropout rates.

The High-Level Findings of Cipriani 2018: All 21 antidepressants studied were more effective than placebo.

Best Balance of Effectiveness and Acceptability of Antidepressants: Escitalopram, Sertraline, Mirtazapine, Agomelatine and Vortioxetine, 

This list of five antidepressants contains three of the drugs found in the 2009 “best of” list escitalopram (Lexapro®), sertraline (Zoloft®) and mirtazapine (Remeron®) and two newcomers agomelatine (Valdoxan® and Thymanax®) and vortioxetine (Trintellix® and Brintellix®).

Here is my commentary on these antidepressants. Agomelatine was never available in Canada because Health Canada never approved it. My reading on agomelatine suggests it is not very effective nor often used even in countries in which it is approved.

Vortioxetine was just being introduced before I retired and by anecdote seems to live up to its selling feature of being an effective antidepressant and helping with cognitive function.

High Effectiveness but Lower Tolerability: Paroxetine, Amitriptyline, Venlafaxine

My commentary on this list is mixed. I stopped prescribing paroxetine (Paxil®) many years ago when patients reported significant discontinuation symptoms. It is an effective antidepressants but getting off it is too difficult to justify its use.

I prescribed a lot of amitriptyline (Elavil®) and venlafaxine (Effexor®) over the years and contrary to the Cipriani study, I found both were generally effective and well tolerated in the ME community. Amitriptyline has many intolerable side effects when used at full antidepressant does (200 – 300 mg) but when used at low does (5 – 25 mg) for assistance with sleep and pain, it is often well tolerated and still has a mild antidepressant effect.

Antidepressants Really Work? The Statistical Reality

There have been thousands of randomized controlled trials of antidepressants, and most show antidepressants have moderate superiority over placebo.

They are 42% more effective than placebo in lessening the symptoms of major depression. I am aware there are dissenting views about this claim - that could be the topic for a future blog post.

They are 70% more effective than placebo at reducing the risk of relapse if continued on a daily basis for up to three years. ​

The Benefit Breakdown of Antidepressants

Analyses suggest that roughly half of observed improvement reflects placebo response, about one quarter reflects natural remission, and approximately one quarter represents the drug’s specific pharmacologic effect (Bschor & Kilarski, 2016).

Important Notes on Safety and Recovery When it Comes to Antidepressants

• Suicide risk: Antidepressants do not reduce suicide rates and may initially increase the risk especially for those under 25 years old.
• The "still not myself" factor: More than 90% of people in "remission" still don't feel like themselves. They typically report three or more residual symptoms, such as sleep disturbance, weight changes, low energy, and cognitive difficulties (Nierenberg et al., 2010).

Why the Number Needed to Treat (NNT) Is Important?

If you are considering a medication, supplement or any new intervention I recommend looking up the “number needed to treat” (NNT) for that drug and your condition. To learn more, go to my blog from November, 2025

The “number needed to treat” (NNT) tells us how many people must be treated for one additional person to benefit beyond placebo. For most antidepressants, the NNT is between 6 and 10 over 12 weeks. This means one additional person improves for every 6–10 treated. A number between 6-10 is considered good and is more favorable than the NNT for many other commonly used medications.

https://thennt.com/home-nnt/ is a free site providing information about many drugs and indications. Try looking up your condition and the drug you are considering to learn what the NNT is.

My Views as a Psychiatrist on Antidepressants and Complex Chronic Diseases

Despite all the cautionary, even discouraging or alarmist information you may hear about antidepressants, in my experience, many people with major depressive disorder benefit. In some cases, antidepressants make a very significant positive difference to quality of life.

It is important to note that medication is most likely to be effective for depression when used as part of a holistic therapeutic program including staying active and connected, getting daily sunlight, eating a healthy diet, having access to safe accommodation and healthy food, developing a positive mindset and managing stress well. Seeking counselling or psychotherapy to help address past and present life problems that may be contributing to depression can be very helpful.

A Critical Warning for the ME/CFS Community: Antidepressants DO NOT Benefit ME/CFS.

Please NOTE, I am talking here about using antidepressants to treat depression. Antidepressants have no place in the treatment of complex chronic diseases unless you also have a mental health condition.

• Exception: Off-label use for insomnia and chronic pain.
• Fact: Antidepressants do not lessen the core symptoms of ME/CFS. If someone tries to convince you otherwise, seek another, more informed practitioner.

Advice for "Messy, Complicated" Humans

Over the decades I have learned that ordinary humans with depression are not the same as carefully selected study participants. We are messy, complicated people living in uncontrolled families and environments with additional health conditions, infectious and toxic exposures, sensitivities and life circumstances to contend with.

If a drug or other treatment doesn't work, it is not your fault. It means that your unique constellation of symptoms and underlying causes have not responded to the treatment even though it helped others.

The bottom line is that mental health treatment is complicated and nuanced. There are no blanket truths. Antidepressants are not miracles, but they do have utility when carefully selected, properly used and tolerated.

What to Look for in a Practitioner.

• Mental health is not a do-it-yourself field. You can flounder for years, decades or even your whole life without proper guidance.
• To make it more complicated, it can be difficult to find knowledgeable practitioners who are a good fit for you.
• Ideally, you need a coordinating clinician (ideally a psychiatrist) who can assess contributing factors, develop an individualized plan, and refer appropriately.
• Most will need an experienced psychotherapist, someone with knowledge about complex chronic diseases so they know what you are going through.
• Look for practitioners who take time to understand your story, build trust, admit uncertainty, adjust when needed, and maintain integrity. These traits are more important than the qualifications of the practitioner.
  
  

Some Final Thoughts: Do Your Due Diligence

• Be cautious when trying new drugs for any condition.
• Understand potential side effects.
• Ask thoughtful questions, and
• Avoid rushing decisions unless the situation is urgent.

If you are a visual/auditory learner, go to the Video Tip corresponding to this blog here.  

 If you liked this blog, you may also like the following similar blogs about mental health and medications:

https://www.eleanorsteinmd.ca/blog/drugs

https://www.eleanorsteinmd.ca/blog/depression

https://www.eleanorsteinmd.ca/blog/safe-effective-sleep-medication

If topics like this are of interest to you, consider joining Live! With Dr. Stein, where you will meet with me every other Thursday to learn about cutting-edge research and accessible strategies to improve your health and quality of life. 

 To learn more about Live! with Dr. Stein, click on the image above.

Dr. Eleanor Stein is a retired physician and psychiatrist who now dedicates her career to empowering people with complex chronic conditions—such as myalgic encephalomyelitis/chronic fatigue syndrome  (ME/CFS), fibromyalgia, environmental sensitivities, long COVID and chronic pain—to reclaim their lives through science-based education using self-management, circadian biology, neuroplasticity, hormesis and quantum biology.

With over 35 years of clinical practice in Calgary, Alberta, Canada, along with research and decades of lived experience navigating ME/CFS, fibromyalgia, and multiple chemical sensitivity (MCS), Dr. Stein uniquely blends rigorous medical insight with personal resilience. Her online resource platform offers self-study programs, webinars, blogs and a podcast to support patients and health care professionals worldwide.

References

Bschor, T., & Kilarski, L. L. (2016). Are antidepressants effective? A debate on their efficacy for the treatment of major depression in adults. Expert Review of Neurotherapeutics, 16(4), 367–374. doi:https://dx.doi.org/10.1586/14737175.2016.1155985

Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., . . . Geddes, J. R. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet, 391(10128), 1357–1366. doi:10.1016/S0140-6736(17)32802-7

Cipriani, A., Furukawa, T. A., Salanti, G., Geddes, J. R., Higgins, J. P., Churchill, R., . . . Barbui, C. (2009). Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet, 373(9665), 746–758. doi:S0140-6736(09)60046-5 [pii];10.1016/S0140-6736(09)60046-5 [doi]

Nierenberg, A. A., Husain, M. M., Trivedi, M. H., Fava, M., Warden, D., Wisniewski, S. R., . . . Rush, A. J. (2010). Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report. Psychol Med, 40(1), 41–50. doi:10.1017/s0033291709006011